RESUMO
A novel series of N-pyridyl amides as potent p38alpha kinase inhibitors is described. Based on the structural similarities between the initial hit and a well-known imidazole pyrimidine series of p38alpha inhibitors, potencies within the newly discovered series were quickly improved by installation of an (S)-alpha-methylbenzyl moiety at the 2-position of the pyridine ring. The proposed binding modes of the new series to p38alpha were evaluated against SAR findings and provided rationale for further development of this series of molecules.
Assuntos
Amidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Amidas/química , Descoberta de Drogas , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Derivatives of the 4-fluorobenzyl dimethylpiperazine-indole class of p38alpha MAP kinase inhibitors are described. Biological evaluation of these compounds focused on maintaining activity while improving pharmacokinetic (PK) properties. Improved properties were observed for structures bearing substitutions on the benzylic methylene.